The developmental mechanisms that lead to under-connectivity, over-connectivity, and mis-connectivity between association regions of the cerebral cortex in autistic spectrum disorder (ASD), attention deficit- hyperactivity disorder (ADHD), schizophrenia (SCZ) and other diseases of cortical circuit development (DCCDs) remain undefined. Our published work from the last phase of this project, plus additional preliminary data, indicates that distinct cortical developmental mechanisms are disrupted in mouse genetic models of DiGeorge/22q11.2 Deletion Syndrome (22q11DS), a genetic syndrome with one of the strongest associations with ASD, ADHD and SCZ vulnerability. We will now test the hypothesis that selective, reversible developmental disruption of connections made by layer 2/3 cortical projection neurons between and within association cortices underlies behavioral changes in mouse models of 22q11 Deletion Syndrome (22q11DS). We will define for the first time the relationship between selectively altered development in association cortices and pathologic changes in neurogenesis, neuronal differentiation, connectivity and behavior in genetic models of ASD, ADHD, and SCZ vulnerability. In Specific Aim 1, we will determine whether altered basal progenitor proliferation selectively diminishes of layer 2/3 cortical projection neuron (cPN) frequency in association regions in 22q11DS mouse models. We will evaluate changes in axon growth and guidance from the diminished population of layer 2/3 cPNs for quantitative and qualitative changes in association cortical connectivity. Our data will establish whether reduced layer 2/3 cPN neurogenesis and related disruption of axon growth account for 22q11DS behavioral pathology due to under-connectivity. In Specific Aim 2, we will determine whether metabolically-mediated changes in layer 2/3 cPN dendritic differentiation disrupt development of local synaptic contacts between layer 2/3 cPNs and key inhibitory or modulatory inputs in association cortical areas. We will assess the contribution of these changes, apparently influenced by distinct 22q11 candidate genes, independent of diminished layer 2/3 cPN genesis to key behavioral impairments in 22q11DS mouse models. In Specific Aim 3, we will assess the feasibility of reversing these developmental changes via pharmacological manipulation of antioxidant defense/reactive oxygen species clearance during development versus adulthood. Our current observations suggest that 22q11 deletion results in oxidative stress and diminished growth in cortical neurons, and that the anti-oxidant N-acetyl cysteine can reverse these effects. Our work will provide a mechanistic foundation for current efforts to use antioxidants as a therapeutic agent for patients with a wide range of DCCDs. Together our results will define the selective contribution of developmental mechanisms that lead to association cortical over/under connectivity versus misconnectivity in ASD, ADHD or SCZ, and the relatively effectiveness of correcting specific developmental deficits for improving behavioral outcomes in DCCDs.